Systems and methods for the treatment of pain through neural fiber stimulation

ABSTRACT

Embodiments of the present invention provide systems and methods for the treatment of pain through activation of select neural fibers. The neural fibers may comprise one or more afferent neural fibers and/or one or more efferent neural fibers. If afferent fibers are stimulated, alone or in combination with efferent fibers, a therapeutically effective amount of electrical stimulation is applied to activate afferent pathways in a manner approximating natural afferent activity. The afferent fibers may be associated with primary receptors of muscle spindles, golgi tendon organs, secondary receptors of muscle spindles, joint receptors, touch receptors, and other types of mechanoreceptors and/or proprioceptors. If efferent fibers are stimulated, alone or in combination with afferent fibers, a therapeutically effective amount of electrical stimulation is applied to activate intrafusal and/or extrafusal muscle fibers, which results in an indirect activation of afferent fibers associated therewith.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/012,254, entitled “Systems and methods for the treatment of painthrough neural fiber stimulation” filed on Feb. 1, 2016, now U.S. Pat.No. 9,707,394, which is a continuation of 14/336,586, entitled “Systemsand methods for the treatment of pain through neural fiber stimulation”filed on Jul. 21, 2014, now U.S. Pat. No. 9,248,289, which is acontinuation of Ser. No. 13/309,152, entitled “Systems and methods forthe treatment of pain through neural fiber stimulation” filed on Dec. 1,2011, now U.S. Pat. No. 8,788,048, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/418,801, filed Dec. 1, 2010,and is entitled “Systems and Methods for the Treatment of Pain ThroughNeural Fiber Stimulation,” and also claims the benefit of U.S.Provisional Patent Application Ser. No. 61/418,768, filed Dec. 1, 2010,and entitled “Systems and Methods to Place One or More Leads in Tissueto Electrically Stimulate Nerves to Treat Pain,” all of which are herebyincorporated by reference. U.S. patent application Ser. No. 13/309,152is a continuation-in-part of co-pending U.S. patent application Ser. No.13/294,875, filed Nov. 11, 2011, and entitled “Systems and Methods toPlace One or More Leads in Tissue to Electrically Stimulate Nerves toTreat Pain,” which claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/412,685, filed Nov. 11, 2010, and entitled“Systems and Methods to Place One or More Leads in Tissue toElectrically Stimulate Nerves to Treat Pain,” which are all incorporatedby reference herein in their entirety.

BACKGROUND OF THE INVENTION

Embodiments according to the present invention relate generally to therelief of bodily pain in an animal, such as a human, and morespecifically to the treatment of pain by action potential activation inneural fibers.

The peripheral nervous system of an animal, such as a human, iscomprised generally of efferent (motor) and afferent (sensory) neuralfibers. Efferent fibers generally carry motor action potentials from thecentral nervous system, while afferent fibers carry sensory actionpotentials to the central nervous system. Since the 1950's and 1960'sand the codification of the gate theory, it has been generally acceptedthat bodily pain results from activity in nociceptive andnon-nociceptive, or somatosensory, afferent nerve fibers, and theinteraction of neural signals and pathways, which are influenced byseveral psychological and physiologic parameters. For instance, in ahealthy person, action potentials transmitted along non-nociceptivefibers do not normally generate or cause a perception of pain. However,in persons experiencing chronic pain (e.g., when a person becomes overlysensitized to pain), non-noxious stimuli, and hence the activity ofnon-nociceptive fibers, can cause pain. This means that in a chronicpain state, sensations that would not be perceived as pain in a healthyperson (e.g. light pressure or touch) may actually be perceived aspainful. That is, in an individual that experiences chronic pain, thenon-noxious stimuli that are sensed (transduced) by non-nociceptivereceptors can lead to a perception of pain. Generally, however, whilenociceptive afferent activity “opens” a gate to the transmission ofsensory action potentials related to noxious input, non-nociceptiveafferent activity “closes” the gate, thereby preventing or inhibitingthe transmission of such sensory signals to the brain, interrupting orreducing the perception of pain.

Prior methods of stimulation of nerves for the reduction of pain,described below, have focused on the stimulation of afferent neuralfibers, and such focus is perhaps understandable due to the conventionalwisdom in the art for the past five decades related to gate controltheory. However, prior nerve stimulation modalities used to treat pain,especially with regards to peripheral nerves, recognized a narrowtreatment window between stimulation settings that may achieve desiredanalgesia through sensory stimulation of non-nociceptive afferents andstimulation settings that reach the threshold for discomfort or motorstimulation of efferent fibers, the latter thought to be undesirable fora number of reasons. Supplementary to such conventional wisdom, and asdescribed in further detail below, recruitment of efferent fibers isthought to be actually beneficial in reducing pain.

The electrical stimulation of nerves, often afferent nerves, toindirectly affect the stability or performance of a physiological systemcan provide functional and/or therapeutic outcomes, and has been usedfor activating target nerves to provide therapeutic relief of pain.While prior systems and methods can provide remarkable benefits toindividuals requiring therapeutic pain relief, many issues and the needfor improvements still remain.

Electrical stimulation systems have been used for the relief of pain.Despite the recognition and use of electrical stimulation for thetreatment of pain, widespread use of available systems is limited. Suchlimited use is thought to stem from a variety of factors, such asinvasiveness of required surgical procedures (e.g. lead placement inepidural space of spinal cord or surgical dissection), risk of surgicalcomplications associated with such procedures (e.g. infection,hemorrhage, neurologic injury, and/or spinal fluid leaks), the technicalskill and training required to place the electrode(s), the duration oftime required to place the electrode(s) correctly, the supportingequipment (e.g. imaging equipment such as fluoroscopy) required forelectrode placement, risk of device complications (e.g. migration ofstimulating lead or catastrophic failure, or breakage, of such lead),and/or loss of pain relief over time.

Electrical stimulation systems may be provided as either external orimplantable devices, or a combination thereof, for providing electricalstimulation to activate nerves to provide therapeutic relief of pain.These “neurostimulators” are able to provide treatment and/or therapy toindividual portions of the body. The operation of these devicestypically includes the use of (i) an electrode placed either on theexternal surface of the skin, and/or (ii) a surgically implantedelectrode. In most cases, one or more surface electrodes, cuff-styleelectrodes, paddle-style electrodes, spinal column electrodes,percutaneous leads, and/or leadless microstimulators incorporatingintegral electrodes, each having one or more electrodes, may be used todeliver electrical stimulation to one or more select portions of apatient's body.

One example of an electrical stimulation system used to treat pain is atranscutaneous electrical nerve stimulation (TENS) system, which hasbeen cleared by the U.S. Food and Drug Administration (FDA) fortreatment of pain. TENS systems are external neurostimulation devicesthat employ electrodes placed on an external skin surface to activatetarget afferent nerve fibers below the skin surface. Advantageously,TENS has a low rate of serious complications, but disadvantageously, italso has a relatively low (i.e., approximately 25% or less) long-termrate of success, and some of its success is attributed to a placeboeffect. Additionally, TENS has low long-term patient compliance becauseit may cause additional discomfort by generating cutaneous pain signalsdue to the electrical stimulation being applied through the skin, theelectrodes may be difficult to apply, and the overall system is bulky,cumbersome, and not suited for long-term use.

In addition, several clinical and technical issues associated withsurface electrical stimulation have prevented it from becoming a widelyaccepted treatment method. First, stimulation of cutaneous painreceptors often cannot be avoided resulting in stimulation-induced painthat limits patient tolerance and compliance. Second, electricalstimulation may be delivered at a relatively high frequency to preventstimulation-induced pain, which leads to early onset of muscle fatiguein turn preventing patients from properly using their muscle(s). Third,it is difficult to stimulate deep nerves and/or muscles with surfaceelectrodes without stimulating overlying, more superficial nerves and/ormuscles resulting in unwanted stimulation. Finally, clinical skill andintensive patient training is required to place surface electrodesreliably on a daily basis and adjust stimulation parameters to provideoptimal treatment. The required daily maintenance and adjustment of asurface electrical stimulation system is a major burden on both patientand caregiver.

Other electrical stimulation systems that have been employed to treatpain include spinal cord stimulation (SCS) systems, which are also FDAapproved as implantable neurostimulation devices marketed in the UnitedStates for treatment of pain. Similar to TENS, when SCS evokesparesthesias that cover a region of pain, it confirms that the locationof the electrode and the stimulus intensity should be sufficient toprovide pain relief and pain relief can be excellent initially, butmaintaining sufficient paresthesia coverage is often a problem due tolead migration along the spinal canal.

Spinal cord stimulation is limited by the invasive procedure and thedecrease in efficacy as the lead migrates. When it can produceparesthesias in the region of pain, spinal cord stimulation is typicallysuccessful initially in reducing pain, but over time the paresthesiacoverage and pain reduction is often lost as the lead migrates away fromits target.

Lead migration is the most common complication for SCS systems,occurring in up to 40% or more of the cases. When the lead migrates, theactive contact moves farther from the target fibers and loses theability to generate paresthesias in the target area. SCS systems attemptto address this problem by using leads with multiple contacts so that asthe lead moves, the next contact in line can be selected to be theactive contact. Additionally, multiple contacts can be used to guide orsteer the current toward the targeted nerve fibers and away from thenon-targeted nerve fibers. Although this approach may be successful, itoften requires time-intensive and complex programming, adding to theoverall cost of the therapy and the burden on the patient andcaregiver(s).

Peripheral nerve stimulation has been attempted and may be effective inreducing pain, but it previously required specialized surgeons to placecuff-or paddle-style leads on or around the nerves in a time-consumingand invasive surgical procedure. Such prior procedures may include theuse of ultrasound-guided lead placement in an attempt to avoid placementin muscle tissue in an attempt to coapt intimately an electrode surfacewith a target nerve, or approximately 3 millimeters or less from thenerve.

Accordingly, the art of pain reduction by neural activation wouldbenefit from systems and methods that improve pain reduction.

SUMMARY OF THE INVENTION

Embodiments of the present invention include improved systems andmethods of pain reduction by inducing action potentials in target neuralstructures. Action potentials may be generated or activated in efferentfibers as an alternative to or in addition to activation of afferentfibers. If an action potential is directly induced in select afferentfibers, such action potentials may be patterned so as to be biomimeticor stochastic, as explained below. Stimulation may be applied totargeted neural fibers located (1) neurologically upstream from aperceived point of pain (i.e. neurologically between the perceived pointof pain and the central nervous system) such as to target neural fibersof nerves of passage, (2) at or near a neurological motor point, and/or(3) neurologically downstream from such motor point, where suchdownstream stimulation may be applied to or near a target region fromwhich a patient is perceiving pain.

A method according to the present invention includes the step ofstimulating efferent nerve fibers to generate an action potential in theefferent nerve fibers in an animal, such as a human, to reduce aperception of pain by the animal. In one embodiment, the stimulatingstep includes electrical stimulation.

According to one aspect of a method according to the present invention,the efferent nerve fibers are located outside a neurological motor pointand outside a central nervous system of the human. The efferent nervefibers may be located between a neurological motor point and the centralnervous system of the human.

According to another aspect of a method according to the presentinvention, the efferent nerve fibers include motor axons, such as Aαaxons that may activate extrafusal muscle fibers and/or Aγ axons thatmay activate intrafusal muscle fibers.

According to still another aspect of a method according to the presentinvention, the method may further include the step of activatingafferent nerve fibers, such as those that are in neural communicationwith neural receptors, such as proprioceptors. The activation of theafferent nerve fibers may result from a transduction of a physiologicalresponse to the step of electrically stimulating efferent nerve fibers.Such physiological response may be a contraction of extrafusal musclefibers or intrafusal muscle fibers.

Another method according to the present invention is a method ofreducing a perception of pain by an animal, such as a human, of ahypersensitized portion of the animal nervous system. Such methodincludes the step of applying electrical stimulation to at least aportion of the nervous system to cause a reduction of perception of painby the animal.

According to still another aspect of a method according to the presentinvention, the applying step ay be performed for a predeterminedtreatment time, and the reduction of perception of pain may occur atleast partially during the treatment time and at least a portion of thereduction of perception of pain may be maintained after the end of thepredetermined treatment time.

According to yet another aspect of a method according to the presentinvention, the animal is a human and the portion of the nervous systemcomprises efferent nerve fibers located neurologically between andoutside a neurological motor point and a central nervous system of thehuman.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts various physiological structures for reference inconnection with the following disclosure.

FIG. 2A depicts an example of a muscle spindle (shown contained in thecapsule), including the intrafusal muscle fibers (innervated by type γ(gamma) (Class Aγ) motor neurons (efferent axons) and by sensory neurons(afferent axons)). The efferent (gamma) axons terminate (shown by GammaMotor Endings) on and innervate the spindle's intrafusal muscle fibers.The sensory endings of the primary (group Ia) afferent axons and asecondary (group II) afferent axons innervate the intrafusal fibers.

FIG. 2B depicts intrafusal motor fibers (nuclear chain fibers andnuclear bag fibers) and their sensory innervation. The group II afferentaxons are shown innervating the nuclear chain fibers and the staticnuclear bag fiber. The group Ia afferent axons are shown wrapping aroundand innervating the nuclear chain fibers, the static nuclear bag fiber,and the dynamic nuclear bag fiber. The figure also indicates whichportions can be considered contractile and non-contractile.

FIG. 2C depicts an example of how stretch alone or in combination withstimulation of a static gamma fiber or a dynamic gamma fiber can changethe neural activity of the respective afferents axons innervating thefibers of the muscle spindle. Activation of gamma motor neurons(efferent axons), which activate the intrafusal muscle fibers, canchange the frequency (Imp/s) of neural activity and stretch-sensitivityof the afferent neurons. The figure also depicts an example of thepossible relative steady-state and dynamic responses that may beachieved in terms of the neural activity of an afferent neuroninnervating a muscle spindle fiber.

FIG. 3 depicts a Golgi tendon organ including collagen fibers thatphysically interact with afferent axons to generate an action potentialthereon during stretch.

FIG. 4A provides a diagrammatic view of electrode placement near atargeted sensory neural structure according to a sensing step of asecond embodiment of a method according to the present invention.

FIG. 4B provides a diagrammatic view of electrode placement near atargeted sensory neural structure according to a stimulating step tooccur after or without the sensing step of FIG. 4A.

FIG. 5 provides a diagrammatic view of electrode placement near atargeted sensory neural structure according to a first embodiment of amethod according to the present invention.

FIG. 6A provides a diagrammatic view of electrode placement near atargeted neural structure according to a third embodiment of a methodaccording to the present invention.

FIG. 6B provides a diagrammatic view of a muscle contraction caused byelectrical stimulation by the electrode of FIG. 6A.

FIG. 7A provides a diagrammatic view of afferent neural structureactivation or firing in response to a muscle stretch.

FIG. 7B provides a diagrammatic view of stretch receptor afferent neuralstructure activation, as perhaps by a weighted stretch, and stretchreceptor afferent neural fiber deactivation during muscle contractioncaused by electrical stimulation of efferent neural structures.

FIG. 7C provides a diagrammatic view of a method of continuing afferentactivation during the contraction of FIG. 7B through stimulation ofadditional or alternative efferent neural structures to those efferentstructures stimulated in FIG. 7B.

FIG. 8 is an idealized, diagrammatic view showing a nerve of passagestimulation system.

FIGS. 9A to 9C are views showing a percutaneous lead that can form apart of a nerve of passage stimulation system.

FIGS. 10A/B and 11A//B are representative leads that can form a part ofa nerve of passage stimulation system.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Although the disclosure hereof is detailed and exact to enable thoseskilled in the art to practice the invention, the physical embodimentsherein disclosed merely exemplify the invention, which may be embodiedin other specific structures. While the preferred embodiment has beendescribed, the details may be changed without departing from theinvention, which is defined by the claims.

As described in the Background section, above, the nervous system of ananimal generally comprises efferent and afferent neural fibers, andprior pain reduction modalities have focused on action potentialgeneration or activation in non-nociceptive afferent neural fibers toinhibit, or “close the gate” to, the transmission of nociceptive painsignals to the brain. This has come to be known as the gate controltheory of pain management. Most afferent fibers, however, are notbundled only with other afferent fibers; rather, the majority of nervesfound amenable to peripheral nerve stimulation are nerve bundlescomprising both afferent and efferent fibers.

With reference also to FIGS. 1-3, electrical stimulation providedaccording to systems and methods of the present invention may mediatepain relief by activating somatosensory pathways that may be associatedwith mechanoreceptors, thermoreceptors, proprioceptors, and/orchemoreceptors. Generally, types of neural cells, axons, nerve fibers,or physiological structures that may be affected, such as by intra-orextra-muscle (e.g., in subcutaneous, connective, adipose, or othertissue) electrical stimulation, include functional afferent types A andC axons and efferent type A axons.

The afferent axons may be classified as Aα (type Ia or Ib), Aβ (typeII), Aδ (type III), or C (type IV). Aα (type Ia) fibers are generallyrecognized as being associated with the primary sensory receptors of themuscle spindle, such as for transducing muscle length and speed. Thesefibers are myelinated, usually having a diameter from about 9 to about22 micrometers (μm), although other diameters have been observed and maybe included, and a conduction velocity of about 50 to about 120 metersper second (m/s), which is known to be proportional to the diameter ofthe fiber for both this type and other types of myelinated fibers. Aα(type Ib) fibers are generally recognized as being associated with Golgitendon organs, such as for transducing muscle contraction. These fibersare myelinated, having a diameter from about 9 to about 22 micrometers(αm) and a conduction velocity of about 50 to about 120 meters persecond (m/s). Aβ (type II) fibers are generally recognized as beingassociated with the secondary sensory receptors of the muscle spindle,such as for transducing muscle stretch. These fibers are also associatedwith joint capsule mechanoreceptors (as transduces joint angle) and allcutaneous mechanoreceptors. The cutaneous mechanoreceptors may includeMeissner's corpuscles, Merkel's discs, Pacinian corpuscles, Ruffinicorpuscles, hair-tylotrich (for sensing stroking/fluttering on the skinor hair), and the field receptor (for sensing skin stretch).

Meissner's corpuscles are nerve endings that can be found in the skin,which transmit afferent information regarding touch (such as soft, orlight, touch) and/or vibration, especially at vibration frequencies ofless than 50 Hertz. These fibers are rapidly adaptive receptors that areoften located below the epidermis within the dermal papillae. Thecorpuscles may be found as encapsulated unmyelinated nerve endings,comprising flattened supportive cells arranged as horizontal lamellaesurrounded by a connective tissue capsule. Examples of this corpusclehave been described as having a length of about 30 to about 140 μm and adiameter of about 40 to about 60 μm.

Merkel's discs are a type of mechanoreceptor found in the skin, hairfollicles, and in the oral and anal mucosa. The discs transmit afferentinformation regarding pressure and texture. Sometimes referred to as aMerkel disc receptor or Merkel cell-neurite complex, the nerve endingcomprises a Merkel cell next to a nerve terminal. A single afferentnerve fiber may innervate multiple nerve endings, such as 50-100endings. This mechanoreceptor is an unencapsulated, slowly adapting typeI mechanoreceptor that will provide a non-or minimally-decaying responseto pressure. The Merkel disc receptor may have two phases of firing,dynamic and static. In the static phase, an irregular activity may beobserved, which may be typical of slowly adapting type Imechanoreceptors but contrasts with the regular pattern of slowlyadapting type II mechanoreceptors.

Pacinian corpuscles are nerve endings that may be found in the skin.They may also be found in the mesentery, between layers of muscle, andon interosseous membranes between bones. Pacinian corpuscles transmitafferent information regarding pain and pressure. For instance, thesecorpuscles may detect gross pressure changes and vibrations and may firein response to quick changes in joint position. They are phasic tactilemechanoreceptors that can detect deep pressure because they are foundbelow the skin surface, usually in the dermis, and comprise some freenerve endings.

Ruffini corpuscles are slowly adapting mechanoreceptors that may bepresent in the glabrous dermis (hairless skin) and subcutaneous tissueof humans. These corpuscles transmit afferent information regarding skinstretch, movement, position (such as position of the fingers), and senseof control (such as slipping of objects along the skin surface). Thistype of receptor may have a spindle shape, and they may be found in thedeep layers of the skin, allowing them to indicate continuous pressurestates and mechanical joint deformation, such as joint angle change.

The Aβ fibers are myelinated, usually having a diameter from about 6 toabout 12 micrometers (μm), although other diameters have been observedand may be included, and a conduction velocity of about 33 to about 75meters per second (m/s).

Aδ (type III) fibers are generally recognized as being associated withfree nerve endings of touch and pressure (for sensing excess stretch orforce), hair-down receptors (for sensing soft, or light, stroking),nociceptors of the neospinothalamic tract, and cold thermoreceptors.These fibers are thinly myelinated, having a diameter from about 1 toabout 5 micrometers (μm) and a conduction velocity of about 3 to about30 meters per second (m/s).

C (type IV) fibers are generally recognized as being associated withnociceptors of the paleospinothalamic tract, and warmth thermoreceptors.These fibers are unmyelinated, having a diameter from about 0.2 to about1.5 micrometers (μm) and a conduction velocity of about 0.5 to about 2.0meters per second (m/s).

As mentioned above, most nerve bundles include both afferent andefferent fibers. The efferent axons may be classified as Aα or Aγ. Aαefferent fibers are generally recognized as being associated withextrafusal muscle fibers. These fibers are myelinated, having a diameterfrom about 13 to about 20 micrometers (μm) and a conduction velocity ofabout 50 to about 120 meters per second (m/s). Aγ efferent fibers aregenerally recognized as being associated with intrafusal muscle fibers.These fibers are myelinated, having a diameter from about 5 to about 8micrometers (μm) and a conduction velocity of about 20 to about 40meters per second (m/s).

A first method according to the present invention includes activatingafferent fibers (e.g. type Ia, Ib, and/or II, which may also be calledAα and/or Aβ afferent fibers), which are physically located in an areafrom or in which an animal is perceiving pain. When a fiber is referredto herein as “activated,” it is to be understood that at least oneaction potential is generated or initiated by or along, or propagatedalong, such fiber in response to some form of stimulation. Such afferentfiber activation may mediate pain relief by activation of afferentpathways associated with primary receptors of muscle spindles, Golgitendon organs, secondary receptors of muscle spindles, joint receptors,touch receptors (e.g. Meissner's corpuscles, Merkel disk receptors,Pacinian corpuscles, Ruffini endings, etc.) other types ofmechanoreceptors (e.g. joint capsule mechanoreceptors), and/orproprioceptors. As a non-limiting example, stimulation may activate oneor more Aβ fibers that carry afferent information from a mechanoreceptor(i.e. a sensory receptor) that responds to mechanical pressure ordistortion. The stimulation may be applied in muscle or in non-muscletissue (e.g. subcutaneous, connective, adipose or other tissue).Non-limiting examples of mechanoreptor pathways that may be activated bystimulation include (1) one or more Pacinian corpuscles; (2) one or moreMeissner's corpuscles; (3) one or more Merkel disc receptors; and/or (4)one or more Ruffini corpuscles. The applied stimulation may mediate painrelief through the activation of nerve fibers associated with, and/orinnervating, receptors that are rapidly adapting, intermediate adapting,and/or slowly adapting. While stimulation may be applied directly totarget nerves, an electrode, as more fully described below, ispreferably spaced a predetermined distance, or within a predeterminedrange of distances, from the target nerve fibers.

A second method according to the present invention comprises the step ofactivating one or more afferent nerve fibers that may be located outsidean area from or in which an animal is perceiving pain, and may or maynot be associated with the mentioned receptors. Such stimulation may bebeneficial to patients experiencing pain in regions no longer innervatedor that were not previously innervated by the target fibers, such asthose patients that may have had removal of, or damage to, theirafferent receptors. Examples of such situation may be amputee phantomlimb pain or tissue damage due to trauma, such as burns, or surgery.Other indications in which such stimulation may provide beneficialperceived reduction in pain are pathological or disease states (e.g.induced by chemotherapy, vascular insufficiency, cancer, or diabetes) orother considerations that may prevent activation of receptors byphysiological transduction. Other considerations my include areas of thebody that are sensory-only areas, such as the sural nerve, or areas inwhich the receptors may be intact, but it may be preferable not toactivate them. For instance, if a nerve trunk (e.g. femoral or sciaticnerve) is being stimulated, large contractions may be undesirable due tothe physical effect of same. Additionally or alternatively, tissuedamage or disease progression dictate or influence the placement ofneedles and/or electrodes; for instance, if a patient suffers fromcomplex regional pain syndrome, it may be desirable to prevent insertionof a needle in the affected area, as it may make symptoms of thesyndrome worse, but a needle may be inserted outside of the affectedarea with less risk.

In any method according to the present invention involving directstimulation of afferent nerve fibers and/or afferent receptors, with orwithout efferent fiber recruitment, the stimulation is preferablyprovided in one or both of two ways: (1) direct mimicked (or biomimetic)afferent stimulation and/or (2) modulated high frequency-inducedstochastic response. With respect to direct mimicked afferentstimulation, stimulation is applied in a predetermined, random, orpseudo-random manner to mimic afferent neural activity that otherwisemay naturally occur in response to activity normally sensed by thetarget afferents. For example, afferents, including type Ia fibersassociated with the muscle spindle (as shown in FIGS. 2A-B) and type Ibfibers associated with Golgi tendon organs (as shown in FIG. 3), andpossibly others, normally respond, and fire multiple, temporallypatterned action potentials in response to a muscle contraction. Topredetermine a stimulation pattern, afferent neural activity—in responseto applied efferent stimulation or cued, or prompted, voluntarilygenerated muscle activity, such as contraction or stretch—may berecorded and/or analyzed, as diagrammatically depicted in FIG. 4A. Therecorded or analyzed pattern may be obtained directly from the animal tobe relieved of pain, may be obtained directly from an animal that is notthe animal to be relieved of pain (live model), may be calculated ormodeled from one or more patterns obtained from one or more animals(including or excluding the animal to be relieved of pain), and/or maybe mathematically or otherwise artificially generated (i.e., withoutsampling). The predetermined pattern of afferent stimulation to beapplied according to the present invention may then be established toapproximate or identically mimic at least a portion of the recorded oranalyzed pattern, as diagrammatically shown in FIG. 4B. Additionally oralternatively, a random or pseudo-random stimulation pattern may beapplied to the afferent fibers to mimic natural afferent activity. Thestimulation patterns applied may include variations in duty cycle and/orin stimulation waveform shape and/or pulse parameters, such asfrequency, pulse width, and/or amplitude, which may be varied betweenapplied pulses, or during a pulse, which may have the effect ofmodifying waveform shapes. Altered stimulation patterns may additionallyor alternatively utilize a pre-pulse, which may be the same or oppositepolarity as a treatment pulse, and may have the same or oppositepolarity thereof. With respect to the second way, specified asmodulated, high-frequency-induced stochastic response and asdiagrammatically depicted in FIG. 5, naturally occurring afferent actionpotentials (occurring in response to stimuli) may be generated orapproximated as a result of an applied electrical stimulation at amodulated high frequency. For example, a relatively high frequency fromabout 1 kHz to about 20 kHz, preferably about 4 kHz, modulated at areduced frequency, such as about 0.1 Hz to about 1 kHz, more preferablyless than 50 Hz, such as 1-30 Hz, and more preferably at about 12-16 Hz,may be used. Such stimulation may generate pseudo-random patterns ofactivity in the affected afferent nerve fibers.

Example of Direct Afferent Action Potential Stimulation

The treatment of pain through direct afferent fiber stimulation maydemonstrate dis-sensitizing of the afferent neural tissues thatnaturally respond to such stimulation. That is, it is generallyrecognized that the perception of pain, especially non-acute pain suchas sub-acute or chronic pain, in mammals can be caused, worsened, and/orsustained in duration by a sensitization of afferent sensory receptorsand/or the central nervous system fibers that receive direct and/orindirect signals from the afferent sensory receptors, including freenerve endings, to noxious or conventional or previously non-noxiousstimuli. Sensitization is the process whereby previously non-noxiousstimuli are perceived as painful, and this is an integral part of thedevelopment and maintenance of chronic pain (as opposed to the acute,healthy pain response). Such sensitization may result fromnon-nociceptive primary afferents (e.g. Aβ) sprouting to makeinappropriate and/or additional connections in the spinal cord, from theloss of inhibition in the central nervous system (e.g. spinal cord,and/or brain), and from plasticity resulting from changes in functionalconnectivity. However, what has been demonstrated by certain afferentfiber stimulation for the treatment of pain is that such stimulation mayactually permanently, or at least long-term, reverse the sensitizationprocess that formed the basis for the chronic pain being treated.Accordingly, the effects of the afferent stimulation for the treatmentof pain chronologically outlast the treatment duration, and such effectsmay exponentially outlast the treatment duration. For example, it iscommon for patients that have a reduced level of pain measured, observedor reported at the end of one month after a treatment cycle, such as athree-week treatment cycle, to demonstrate the same level of painreduction up to one year or longer after the treatment cycle hasconcluded. Thus, dis-sensitization may be demonstrated and the painreduction experienced at approximately the stimulation treatmentduration after the end of the treatment cycle is maintained for morethan 17 times the treatment duration. For example, if a patient reporteda pain level of 6 prior to treatment, and a pain level of 2 at a timethat is about one month after a treatment cycle (such as a three-weektreatment cycle), there has been demonstrated a high probability thatthe patient will report a pain level of 2 at a time that is about oneyear after the completion of the treatment cycle. In any event, at oneyear after treatment, if the pain level reported by the patient is lessthan the pain level reported prior to treatment, then at least somedis-sensitization is thought to have occurred. Systems and methodsaccording to the present invention may be used to treat pain felt in agiven region of the body by stimulating neural fibers associated with,disposed on, or innervating muscle, subcutaneous, connective, adipose,or other tissue that may be close to or some distance away from a “nerveof passage” in a region that is superior (i.e., cranial or upstreamtoward the spinal column) to the region where pain is felt. Neuralimpulses comprising pain felt in a given muscle, organ, or cutaneousregion of the body pass through spinal nerves that arise from one ormore nerve plexuses. The spinal nerves in a nerve plexus, which comprisetrunks that divide by divisions and/or cords into branches, comprise“nerves of passage.” It has been discovered that applying stimulation ina muscle near a targeted nerve of passage relieves pain that manifestsitself in a region that is inferior (i.e., caudal or downstream from thespinal column) from where stimulation is actually applied. An example ofnerves of passage stimulation may be found in U.S. patent applicationSer. No. 12/653,023, filed on Dec. 7, 2009, and entitled “Systems andMethods to Place One or More Leads in Tissue to Electrically StimulateNerves of Passage to Treat Pain,” published as US2010/0152808 and nowU.S. Pat. No. 8,954,153, which is incorporated by reference herein inits entirety

Alternatively or additionally, to relieve pain in a target muscle, thepercutaneous or implanted lead and/or electrode may be placed in themuscle (e.g. deltoid) that is experiencing the pain near, or within atherapeutically effective distance from, the point where a motor nerveenters the muscle (i.e., the motor point).

Phantom pain (a type pain that may be experienced, e.g.,post-amputation) is one example of the effectiveness of “nerves ofpassage” stimulation, because the bodily area in which phantom pain isperceived to originate does not physically exist. A lead and/orelectrode cannot be physically placed in the muscles that hurt, becausethose muscles were amputated. Still, by applying stimulation in amuscle, subcutaneous, connective, adipose, or other tissue that has notbeen amputated at a therapeutically effective distance from a targetednerve of passage that, before amputation, preferably natively innervatedthe amputated muscles, phantom pain can be treated. An example of thetreatment of post-amputation pain may be found in U.S. patentapplication Ser. No. 12/653,029, filed Dec. 7, 2009, and entitled“Systems and Methods To Place One or More Leads in Tissue for ProvidingFunctional and/or Therapeutic Stimulation,” published as US2010/0152809,which is incorporated by reference herein in its entirety.

Chronic, sub-acute, or acute pain in existing, non-amputated muscle,subcutaneous, connective, adipose, or other tissue can also be treatedby “nerves of passage” stimulation. By applying stimulation to or near atargeted nerve of passage that innervates the region where chronic,sub-acute, or acute pain is manifested, the pain can be treated.

In “nerves of passage” stimulation, a lead and/or electrode can beplaced in muscle, subcutaneous, connective, adipose, or other tissuethat is conveniently located near a nerve trunk that passes by theelectrode and/or lead on the way to the painful area. In “nerves ofpassage” stimulation, the lead and/or electrode may be placed in amuscle, subcutaneous, connective, adipose, or other tissue that is notnecessarily the target (painful) tissue, but rather in a muscle or othertissue that is upstream from the painful region, because the proximalmuscle or other tissue presents a convenient and useful location toplace the lead and/or electrode. Additionally or alternatively, the leadand/or electrode may be placed in a muscle, subcutaneous, connective,adipose, or other tissue having more than one region, to stimulate anerve to treat the perception of pain from a different region of thesame muscle or tissue. For instance, with respect to a Sartorius muscle,an electrode may be placed generally near the top of the leg (nearfemoral nerve (1-2 cm below femoral crease)) in a first region of theSartorius muscle, to relieve pain felt in the inner thigh near the knee(downstream), in a second region of the Sartorius muscle.

The systems and methods make possible the treatment of chronic or acutepain in which muscle contraction cannot or should not be evoked (e.g. inthe case of amputation pain in which the target area has been amputatedis no longer physically present) or is otherwise undesirable, or othercases of nerve damage either due to a degenerative diseases or conditionsuch as diabetes of impaired vascular function (in which the nerves aredegenerating, and may be progressing from the periphery), or due totrauma. The systems and methods make possible the placement of one ormore stimulation leads and/or electrodes in regions distant from themotor point or region of pain, e.g., where easier access or morereliable access or a clinician-preferred access be accomplished; or insituations where the motor nerve point is not available, damaged,traumatized, or otherwise not desirable; or in situations where it isdesirable to stimulate more than one motor point with a single leadand/or electrode; or for cosmetic reasons; or to shorten the distancebetween the lead and its connection with a pulse generator; or to avoidtunneling over a large area or over or across a joint, where the lattermay contribute to device failure.

A third method according to the present invention, as diagrammaticallydepicted in FIGS. 6A-B, comprises the step of activating one or moremotor (efferent) axons (type Aα or Aγ) which can, in turn, mediate painrelief by activating extrafusal muscle fibers and/or intrafusal musclefibers. Activation of extrafusal muscle fibers (e.g. via activation ofmotor (Aα) axons) can generate and/or modulate responsive afferentactivity by contracting muscle fibers, producing tension, and/or causingskeletal movement. The action (e.g. contraction, tension, movement,etc.) produced by efferent activity may be transduced by sensory endingsor fibers and transmitted via afferent fibers to the central nervoussystem, which can mediate pain relief. Activation of intrafusal musclefibers (e.g. via activation of motor (Aγ) axons) can modulate and/orgenerate afferent activity by changing afferent firing rate or pattern(e.g. the relative base or steady-state firing frequency, averagethereof, and/or the transient firing frequency such that the runningaverage may or may not vary over time according to a pattern ornon-patterned sequence) and/or the afferent's sensitivity to mechanicalor other stimuli such as stretch, vibration, muscle contraction, etc.One method of providing pain relief is to activate neurons (or neuralstructures) innervating (or considered part of) proprioceptors,modifying proprioception. In either case, of activation of intrafusal(via Aγ efferent axons) and/or extrafusal (via Aα efferent axons) musclefibers, the neural receptors (associated with or innervated by afferentaxons) are allowed to naturally perceive and transduce the effects ofsuch stimulation. Accordingly, methods according to the third embodimentof a method according to the present invention may be said to enhance areduction in pain perception through muscle contraction, which may ormay not be perceptible to the naked eye. It may be possible to detectthe muscle contraction with electromyography (EMG) equipment. The musclecontraction, in turn, may cause natural afferent neural activity inresponse, thereby mediating pain relief. Electrical stimulation ofefferent neural structures may or may not recruit afferent fiberactivation. That is, a method according to the present invention mayinclude a step of recruiting or activating one or more sensory, afferentaxons while generating or causing a generation of an action potential inone or more motor, efferent axons. Alternatively, only efferent axonsmay be recruited by stimulation. For instance, when disease (e.g.diabetes or vascular insufficiency), trauma, or another disorder hasimpaired (or eliminated) the response of large diameter afferents (whichare typically thought to respond “first”—at low levels of stimulation),electrical stimulation activation of only efferent fibers may achieve“physiological” activation of other afferents in response to the evokedextrafusal (muscle contraction) or intrafusal activity.

Indeed, the treatment of pain through efferent fiber stimulation maydemonstrate at least partial dis-sensitization (e.g., partial, orcomplete, temporary or permanent reduction of neurologicalhypersensitization) of at least a portion of the nervous system throughactivation of afferent neural tissues that naturally respond to suchstimulation. That is, it is generally recognized that the perception ofpain in mammals is caused by a sensitization of afferent sensoryreceptors, including free nerve endings, to noxious or conventional orpreviously non-noxious stimuli. Sensitization is the process wherebypreviously non-noxious stimuli are perceived as painful, and this is anintegral part of the development and maintenance of chronic pain (asopposed to the acute, healthy pain response). Such sensitization mayresult from non-nociceptive primary afferents (e.g. Aβ) afferentssprouting to make additional connections in the spinal cord, from theloss of inhibition in the spinal cord, and/or from central (brain)plasticity resulting from changes in functional connectivity. However,what has been demonstrated by efferent fiber stimulation for thetreatment of pain is that such stimulation may actually permanently, orat least long-term, reverse the sensitization process that formed thebasis for the chronic pain being treated. Dis-sensitization resultingfrom efferent fiber stimulation may reverse these changes throughalterations in the peripheral and/or central nervous systems, includingbut not limited to changes in the sensitivity of peripheral sensoryreceptors, changes in synaptic connectivity, changes in synapticstrength, and changes in the rate and pattern of neural activity. Inresponse to therapy according to the present invention, the firingpattern and rate of peripheral nervous system (PNS) (e.g. afferent)fibers may change, the firing pattern and rate of central nervous system(CNS) fibers may change, and/or there may be changes in both the PNS &CNS. Additionally or alternatively, there may be changes in thethreshold required to active the fibers (in the PNS, CNS, &/or both PNS& CNS). Accordingly, the effects of the efferent stimulation for thetreatment of pain chronologically outlast the treatment duration, andsuch effects may exponentially outlast the treatment duration. Forexample, it is common for patients that have a reduced level of painmeasured, observed or reported at the end of one month after a treatmentcycle, such as a three-week treatment cycle, to demonstrate the samelevel of pain reduction up to one year or longer after the treatmentcycle has concluded. Thus, this lasting effect is thought to demonstratedis-sensitization, and the pain reduction experienced at approximatelythe stimulation treatment duration after the end of the treatment cyclemay be maintained for more than 17 times the treatment duration. Forexample, if a patient reported a pain level of 6 prior to treatment, anda pain level of 2 at a time that is about one month after a treatmentcycle (such as a three-week treatment cycle), there has beendemonstrated that the patient may report a pain level of 2 at a timethat is about one year after the completion of the treatment cycle. Inany event, at one year after treatment, if the pain level reported bythe patient is less than the pain level reported prior to treatment,then at least some dis-sensitization is thought to have occurred.

Systems and Methods

Various systems may be utilized to implement the stimulation methodsprovided herein. The methods may be carried out in a staged progression,which may include a percutaneous and/or transcutaneous phase. Thepercutaneous and/or transcutaneous stimulation phase may be followed byan implanted, percutaneous, and/or transcutaneous stimulation phase.Preferred percutaneous systems may be found in U.S. patent applicationSer. No. 12/462,384, published as U.S. Patent Application Publication2010/0036445A1 and now U.S. Pat. No. 8,463,383, which is incorporatedherein by reference in its entirety, and/or U.S. patent application Ser.No. 11/595,596, published as U.S. Patent Application Publication2007/0123952A1 and now U.S. Pat. No. 7,810,571, which is incorporated byreference herein in its entirety, and/or U.S. patent application Ser.No. 13/095,616, which is incorporated by reference herein in itsentirety. A preferred implanted system may be found in U.S. Pat. No.7,239,918, which is incorporated herein by reference in its entirety.Another preferred percutaneous stimulation system may be found in U.S.patent application Ser. No. 12/324,044, published as U.S. PatentApplication Publication 2009/0157151A1, which is incorporated herein byreference in its entirety.

Control of a stimulator and/or stimulation parameters according to thepresent invention may be provided by one or more external controllers.In the case of an external stimulator, the controller may be integratedwith the external stimulator. In the case of an implanted stimulator, animplanted pulse generator external controller (i.e., clinicalprogrammer) may be a remote unit that uses RF (Radio Frequency) wirelesstelemetry communications (rather than an inductively coupled telemetry)to control the implanted pulse generator. The external or implantablepulse generator may use passive charge recovery to generate thestimulation waveform, regulated voltage (e.g., 10 mV to 20 V), and/orregulated current (e.g., about 10 μA to about 50 mA). Passive chargerecovery is one method of generating a biphasic, charge-balanced pulseas desired for tissue stimulation without severe side effects due to aDC component of the current.

The neurostimulation pulse may by monophasic, biphasic, and/ormulti-phasic. In the case of the biphasic or multi-phasic pulse, thepulse may be symmetrical or asymmetrical. Its shape may be rectangularor exponential or a combination of rectangular and exponentialwaveforms. The pulse width of each phase may range between e.g., about0.1 μsec. to about 1.0 sec., as non-limiting examples. The preferredneurostimulation waveform is cathodic stimulation (though anodic maywork), biphasic, and asymmetrical.

Pulses may be applied in continuous or intermittent trains (i.e., thestimulus frequency changes as a function of time). In the case ofintermittent pulses, the on/off duty cycle of pulses may be symmetricalor asymmetrical, and the duty cycle may be regular and repeatable fromone intermittent burst to the next or the duty cycle of each set ofbursts may vary in a random (or pseudo random) fashion. Varying thestimulus frequency and/or duty cycle may assist in warding offhabituation because of the stimulus modulation.

The stimulating frequency may range from e.g., about 1 Hz to about 300Hz, or even as high as about 20 kHz to obtain a stochastic response, andthe frequency of stimulation may be constant or varying. In the case ofapplying stimulation with varying frequencies, the frequencies may varyin a consistent and repeatable pattern or in a random (or pseudo random)fashion or a combination of repeatable and random patterns.

In a representative embodiment, the stimulator is set to an intensity(e.g. 1-2 mA (or 0.1-40 mA, or 0.01-200 mA), 100-300 μs (or 40-1000 μs,or 1-10,000 μs)) sufficient to activate the targeted efferent orafferent neural structures, using an electrode that is preferably spacedat some distance (e.g. 1 mm) away from the targeted structure.Additionally or alternatively, an electrode may be placed in directcontact with a target neural structure. If the stimulus intensity is toogreat, it may generate large muscle twitches or contractions sufficientto disrupt correct placement of the lead. If stimulus intensity is toolow, the lead may be advanced too close to the targeted nerve of passage(beyond the optimal position), possibly leading to incorrect guidance,nerve damage, mechanically evoked sensation (e.g. pain and/orparesthesia) and/or muscle contraction, inability to activate the targetnerve fiber(s) without activating non-target nerve fiber(s), improperplacement, and/or improper anchoring of the lead (e.g. the lead may betoo close to the neural structure and no longer able to anchorappropriately in the targeted anchoring tissue, such as muscle oradipose tissue).

In a representative embodiment, the stimulator may be set to a frequency(e.g. 0.5-12 Hz (or 0.1-20 Hz, or 0.05-40 Hz)) low enough to evokevisible muscle twitches (i.e. non-fused muscle contraction) and/ormuscle contraction(s) of the targeted muscle(s) innervated by the targetnerve of passage, but high enough that the targeted nerve will beactivated before the lead is advanced beyond an optimal position,preferably spaced from the nerve. An Example of preferred stimulationparameters are as follows:

Adjusts in increments Parameter Default Minimum Maximum of Amplitude 20mA 1 mA 20 mA 1 mA Frequency 12 Hz 5 Hz 25 Hz 1 Hz Pulse 20 μsec 20 μsec200 μsec 10 μsec Duration Minimum Pulse Pulse Pulse 200 usec 10 μsecDuration Duration Duration Maximum Minimum Minimum Pulse Pulse PulsePulse 10 μsec Duration Duration Duration Duration Normal Minimum MinimumMaximum Therapy 6 hours 15 min 12 hours 15 min Time Duty Cycle 50% 50%50% NA

To position an electrode in vivo, preferably while stimulation is beingapplied, the lead (non-limiting examples of the lead could include asingle or multi-contact electrode that is designed for temporary(percutaneous) or long-term (implant) use or a needle electrode (usedfor in-office testing only)) may be advanced (e.g. slowly advanced)towards the targeted nerve until a desired indicator response (e.g.muscle twitch, muscle contraction, patient sensation, and/or somecombination) is obtained, thereby defining an optimal placementposition. The intensity may then be decreased (e.g. gradually decreased)as the lead is advanced (e.g. advanced slowly) closer to the targetednerve until the desired indicator response(s) may be obtained at smallerintensity(ies) within the target range (e.g. 0.1-1.0 mA (or 0.09-39 mA,or 0.009-199 mA), 100-300 μs (or 40-1000 μs, or 1-10,000 μs)) at somedistance (e.g. X2 mm, where X2<X1, and (as a non-limiting example) X1may be multiple times larger than X2, such as X1≧2*X2, or X1≧5*X2, orX1≧20*X2) from the target nerve. If specific response(s) (e.g. desiredresponse(s) and/or undesired response(s)) can be obtained at a range ofintensities that are too low, then the lead may be located in anon-optimal location (e.g. too close to the target nerve(s)).Non-limiting examples of ranges of intensities that may be consideredtoo low include those that are a fraction (e.g. <⅔, or <⅕, or < 1/10) ofthe intensities that obtained the desired response(s) at X1.

The preferred stimulus intensities are a function of many variables, aremeant to serve as non-limiting examples only, and may need to be scaledaccordingly. As an example, if electrode shape, geometry, or surfacearea were to change, then the stimulus intensities may need to changeappropriately. For example, if the intensities were calculated for alead with an electrode surface area of approximately 20 mm², then theymay need to be scaled down accordingly to be used with a lead with anelectrode surface area of 0.2 mm² because a decrease in stimulatingsurface area may increase the current density, increasing the potentialto activate excitable tissue (e.g. target and non-target nerve(s) and/orfiber(s)). Alternatively, if the intensities were calculated for a leadwith an electrode surface area of approximately 0.2 mm², then theintensities may need to be scaled up accordingly to be used with a leadwith an electrode surface area of 20 mm². Alternatively, stimulusintensities may need to be scaled to account for variations in electrodeshape or geometry (between or among electrodes) to compensate for anyresulting variations in current density. In a non-limiting example, theelectrode contact surface area may be 0.1-20 mm², 0.01-40 mm², or0.001-200 mm². In a non-limiting example, the electrode contactconfiguration may include one or more of the following characteristics:cylindrical, conical, spherical, hemispherical, circular, triangular,trapezoidal, raised (or elevated), depressed (or recessed), flat, and/orborders and/or contours that are continuous, intermittent (orinterrupted), and/or undulating.

Stimulus intensities may need to be scaled to account for biologicalfactors, including but not limited to patient body size, weight, mass,habitus, age, and/or neurological condition(s). As a non-limitingexample, patients that are older, have a higher body-mass index (BMI),and/or neuropathy (e.g. due to diabetes) may need to have stimulusintensities scaled higher (or lower) accordingly.

As mentioned above, if the lead is too far away from the targeted nerve,then stimulation may be unable to evoke the desired response (e.g.muscle contraction(s), comfortable sensation(s), and/or pain relief) inthe desired region(s) at the desired stimulus intensity(ies). If thelead is too close to the targeted nerve, then stimulation may be unableto evoke the desired response(s) (e.g. muscle contraction(s),comfortable sensation(s), and/or pain relief) in the desired region(s)at the desired stimulus intensity(ies) without evoking undesirableresponse(s) (e.g. unwanted and/or painful muscle contraction(s),sensation(s)), increase in pain, and/or generation of additional pain inrelated or unrelated area(s)). In some cases, it may difficult to locatethe optimal lead placement (or distance from the targeted nerve) and/orit may be desirable to increase the range stimulus intensities thatevoke the desired response(s) without evoking the undesired response(s)so alternative stimulus waveforms and/or combinations of leads and/orelectrode contacts may be used. A non-limiting example of alternativestimulus waveforms may include the use of a pre-pulse to increase theexcitability of the target fiber(s) and/or decrease the excitability ofthe non-target fiber(s).

FIG. 8 shows a system useful in implementing the methods disclosedherein. The system and method place the one or more leads 12(B) with itselectrode 14(B) in the targeted muscle in electrical proximity to butspaced away from the targeted nerve of passage. The system and methodapply electrical stimulation through the one or more stimulationelectrodes to electrically activate or recruit the targeted nerve ofpassage that conveys the neural impulses comprising the pain to thespinal column.

It is to be appreciated that the sensation could be described with otherwords such as buzzing, thumping, etc. Evoking paresthesias in the regionof pain confirms correct lead placement and indicates stimulus intensityis sufficient to reduce pain. Inserting a lead 12 percutaneously allowsthe lead 12 to be placed quickly and easily, and placing the lead 12 ina peripheral location, i.e., muscle, where it is less likely to bedislodged, addresses the lead migration problems of spinal cordstimulation that result in decreased paresthesia coverage, decreasedpain relief, and the need for frequent patient visits for reprogramming.

Placing the lead 12 percutaneously in muscle in electrical proximity tobut spaced away from the targeted nerve of passage minimizecomplications related to lead placement and movement. In a percutaneoussystem, an electrode lead 12, such as a coiled fine wire electrode leadmay be used because it is minimally-invasive and well suited forplacement in proximity to a nerve of passage. The lead can be sized andconfigured to withstand mechanical forces and resist migration duringlong-term use, particularly in flexible regions of the body, such as theshoulder, elbow, and knee.

As FIG. 9A, shows, the electrode lead can comprise, e.g., a fine wireelectrode 14, paddle electrode, intramuscular electrode, orgeneral-purpose electrode, inserted via a needle introducer 30 orsurgically implanted in proximity of a targeted nerve of passage. Onceproper placement is confirmed, the needle introducer 30 may be withdrawn(as FIGS. 9B and 9C show), leaving the electrode in place. Stimulationmay also be applied through a penetrating electrode, such as anelectrode array comprised of any number (i.e., one or more) ofneedle-like electrodes that are inserted into the target site. In bothcases, the lead may placed using a needle-like introducer 30, allowingthe lead/electrode placement to be minimally invasive.

In a representative embodiment, the lead 12 comprises a thin, flexiblecomponent made of a metal and/or polymer material. By “thin,” it iscontemplated that the lead should not be greater than about 0.75 mm(0.030 inch) in diameter.

The lead 12 can comprise, e.g., one or more coiled metal wires with inan open or flexible elastomer core. The wire can be insulated, e.g.,with a biocompatible polymer film, such as polyfluorocarbon, polyimide,or parylene. The lead is desirably coated with a textured,bacteriostatic material, which helps to stabilize the lead in a way thatstill permits easy removal at a later date and increases tolerance.

The lead 12 may be electrically insulated everywhere except at one(monopolar), or two (bipolar), or three (tripolar), for example,conduction locations near its distal tip. Each of the conductionlocations may be connected to one or more conductors that run the lengthof the lead and lead extension 16 (see FIG. 9C), proving electricalcontinuity from the conduction location through the lead 12 to anexternal pulse generator or stimulator 28 (see FIG. 9C) or an implantedpulse generator or stimulator 28.

The conduction location or electrode 14 may comprise a de-insulated areaof an otherwise insulated conductor that runs the length of an entirelyinsulated electrode. The de-insulated conduction region of the conductorcan be formed differently, e.g., it can be wound with a different pitch,or wound with a larger or smaller diameter, or molded to a differentdimension. The conduction location or the electrode 14 may comprise aseparate material (e.g., metal or a conductive polymer) exposed to thebody tissue to which the conductor of the wire is bonded.

The lead 12 desirably possess mechanical properties in terms offlexibility and fatigue life that provide an operating life free ofmechanical and/or electrical failure, taking into account the dynamicsof the surrounding tissue (i.e., stretching, bending, pushing, pulling,crushing, etc.). The material of the electrode desirably discourages thein-growth of connective tissue along its length, so as not to inhibitits withdrawal at the end of its use. However, it may be desirable toencourage the in-growth of connective tissue at the distal tip of theelectrode, to enhance its anchoring in tissue.

One embodiment of the lead 12 shown in FIG. 10A may comprise a minimallyinvasive coiled fine wire lead 12 and electrode 14. The electrode 14 mayalso include, at its distal tip, an anchoring element 48. In theillustrated embodiment, the anchoring element 48 takes the form of asimple barb or bend (see also FIG. 9C).

The anchoring element 48 is sized and configured so that, when incontact with tissue, it takes purchase in tissue, to resist dislodgementor migration of the electrode out of the correct location in thesurrounding tissue.

Desirably, the anchoring element 48 is prevented from fully engagingbody tissue until after the electrode 14 has been correctly located anddeployed.

An alternative embodiment of an electrode lead 12 shown in FIGS. 11A and11B, may also include, at or near its distal tip or region, one or moreanchoring element(s) 70. In the illustrated embodiment, the anchoringelement 70 takes the form of an array of shovel-like paddles or scallops76 proximal to the proximal-most electrode 14 (although a paddle 76 orpaddles could also be proximal to the distal most electrode 14, or couldalso be distal to the distal most electrode 14). The paddles 76 as shownare sized and configured so they will not cut or score the surroundingtissue. The anchoring element 70 is sized and configured so that, whenin contact with tissue, it takes purchase in tissue, to resistdislodgement or migration of the electrode out of the correct locationin the surrounding tissue (e.g., muscle 54). Desirably, the anchoringelement 70 is prevented from fully engaging body tissue until after theelectrode 14 has been deployed. The electrode is not deployed untilafter it has been correctly located during the implantation (leadplacement) process, as previously described. In addition, the lead 12may include one or more ink markings 74, 75 (shown in FIG. 11A) to aidthe physician in its proper placement.

The introducer 30 (see FIG. 9A) may be insulated along the length of theshaft, except for those areas that correspond with the exposedconduction surfaces of the electrode 14 housed inside the introducer 30.These surfaces on the outside of the introducer 30 are electricallyisolated from each other and from the shaft of the introducer 30. Thesesurfaces may be electrically connected to a connector 64 at the end ofthe introducer body (see FIG. 9A). This allows connection to an externalstimulator 28 (shown in FIG. 9A) during the implantation process.Applying stimulating current through the outside surfaces of theintroducer 30 provides a close approximation to the response that theelectrode 14 will provide when it is deployed at the current location ofthe introducer 30.

The introducer 30 may be sized and configured to be bent by hand priorto its insertion through the skin. This will allow the physician toplace lead 12 in a location that is not in an unobstructed straight linewith the insertion site. The construction and materials of theintroducer 30 allow bending without interfering with the deployment ofthe lead 12 and withdrawal of the introducer 30, leaving the lead 12 inthe tissue.

Those skilled in the art will recognize that, for simplicity andclarity, the full structure and operation of all devices and processessuitable for use with the present invention is not being depicted ordescribed herein. Instead, only so much of an implantable pulsegenerator and supporting hardware as is unique to the present inventionor necessary for an understanding of the present invention is depictedand described. The remainder of the construction and operation of theIPGs described herein may conform to any of the various currentimplementations and practices known in the art.

Pain relief provided by systems and methods according to the presentinvention may be correlated to an analysis of quality of life of theanimal receiving such relief. It may be important to measure thehealth-related quality of life (HRQOL), as pain is known to impact evenotherwise simple, daily activities. There is a plurality of generallyaccepted methodologies for measuring improvements in a patient's qualityof life. One methodology includes analysis of patient responses to oneor more questions from an SF-36 Health Survey, available from QualityMetric, Inc., of Lincoln, R.I. The SF-36 is a generic health survey of36 items designed to assess basic physical functioning and emotionalwell-being regardless of the disease or treatment. The 36 items aregrouped into eight domains: physical functioning, role limitations dueto physical problems, social functioning, bodily pain, general mentalhealth, role limitations due to emotional problems, vitality, andgeneral health perceptions. The items include questions related to thefollowing:

present and comparative general health;

frequency and severity of physical health or emotional limitations ontypical daily activities, such as stair-climbing, personal positioningsuch as squatting or kneeling, walking, and maintenance of personalhygiene;

amount of bodily pain and interference of such pain on daily and socialactivities;

comparison of general health to others; and

feelings such as nervousness, peacefulness, amount of energy, depressionor happiness, and exhaustion.

Generally, the ratings provided by the patient are on scales of, e.g., 1to 3, or 1 to 5.

Another methodology of correlating treatment to quality of life involvesan analysis of data from the Pain Disability Index (PDI), which is avalidated survey that measures the degree to which pain disruptsactivities such as work and athletics. Many patients with chronic painbelieve increased ability to function physically is an importantobjective for pain treatment, and assessment of the impact of pain onphysical functioning is recommended as one of the core outcome measuresin chronic pain studies. The PDI is considered a simple and rapid toolfor evaluating the impact that pain has on physical functioning. The PDIprovides patient feedback related to the impact of pain on sevencategories of life activity. Generally, each category is rated on a zeroto ten scale, where zero indicates no disability at all in such lifeactivity and ten indicates that a patient has been prevented fromengaging in all activities of the category. The seven categories of thePDI are:

Chores and errands: This category refers to activities of relatedgenerally to home life and/or family. It includes chores or dutiesperformed around the house (e.g., yard work, dusting, laundry) anderrands or favors for other family members (e.g., driving the childrento school, grocery shopping);

Leisure time: This category includes athletics, hobbies, and othersimilar recreation;

Social activity: This category refers to interaction with friends andacquaintances other than family members, such as attendance at parties,a theater, concerts, restaurants, and other social functions;

Job-related activities: This category refers to activities that are apart of or directly related to one's job, whether or not it is a paying,non-paying or volunteer career;

Sexual behavior: This category refers to the frequency and quality ofone's sex life;

Personal maintenance: This category includes activities related toindependent daily living (e.g. taking a shower, driving, gettingdressed, shaving, etc.); and

Life-sustaining behavior: This category refers to basic behaviors suchas eating, sleeping, and breathing.

Alternatively or additionally, other validated measurements or surveys,such as the Brief Pain Inventory-Short Form (BPI-SF) or Brief PainInventory-Long Form (BPI-LF), may be used. For instance, BPI-SF (or -LF)question number 3 requests that patients rate the worst pain they haveexperienced in the past week on a scale from zero to ten, where zeroindicates “no pain” and ten indicates “pain as bad as you can imagine.”Alternatively or additionally, BPI-SF question 9 requests that patientsrate, on a scale of zero to ten, the interference of pain on variousactivities. A rating of zero indicates that pain has no interference onthe activity and a rating of ten indicates that pain completelyinterferes with such activity. Such survey may include ratings ofinterference on activities such as general activity, walking ability,normal work (inside and outside the home), sleep, and interpersonalrelations. Further such survey may include ratings of personal feelings,such as the pain interference with mood or enjoyment of life. Where allseven eleven-point-scale ratings are included, a mean score between zeroand ten may be calculated by summing the seven ratings and dividing byseven.

The quality of life surveys are preferably administered both before andafter a treatment period, and the results thereof are compared. Forinstance, if the BPI-SF (or-LF) question 9 is used, a comparison of thepost-treatment mean and the pre-treatment mean may indicate a level ofsuccess of the treatment. As used herein, post-treatment may refer toany time after the start of treatment, including but not limited toafter completion of a treatment period, duration, regime, or protocol.On the eleven-point (0-10) mean scale of the BPI-SF question 9, it ispreferable to have an improvement (reduction) of more than one point outof the total ten possible points, more preferably to have an improvementof more than two points, and most preferred to have an improvement ofmore than three points. After any mid-or post-treatment quality of lifeanalysis, stimulation parameters or methodologies may be altered, andthe quality of life may again be examined, and compared to baseline(prior to receipt of any treatment) and/or to other post-treatmentresults to determine whether the altered parameters were any more orless effective than the first in improving quality of life.

The foregoing is considered as illustrative only of the principles ofthe invention. Furthermore, since numerous modifications and changeswill readily occur to those skilled in the art, it is not desired tolimit the invention to the exact construction and operation shown anddescribed. While the preferred embodiment has been described, thedetails may be changed without departing from the invention, which isdefined by the claims.

Having thus described the invention, we claim:
 1. A system for reducingthe perception of pain in a human by generating action potentials intargeted nerve fibers with electrical stimulation while avoiding actionpotential in non-targeted nerve fibers comprising: a percutaneous leadcarrying a single contact electrode proximate to a distal tip of thelead; and pulse generator connected to the lead delivering electricalstimulation to the electrode at an intensity between 0.1 mA and 40 mAand having a monophasic, bisphasic, or multi-phasic pulse with a pulsewidth between 40 μs and 1000 μs and waveform shape that is rectangular,exponential, or a combination of rectangular and exponential.
 2. Thesystem of claim 1 further comprising an introducer.
 3. The system ofclaim 1 wherein the percutaneous lead includes a coiled metal wire withan open core.
 4. The system of claim 3 wherein the wire includes atleast one material selected from polyfluorocarbon, polyimide, parylene,and a textured bacteriostatic material.
 5. The system of claim 3 whereinthe percutaneous lead has a diameter of 0.75 mm or less.
 6. The systemof claim 1 wherein the percutaneous lead is insulated.
 7. The system ofclaim 6 wherein a portion of the percutaneous lead is de-insulated toform the single electrode.
 8. The system of claim 7 wherein the distaltip includes an anchoring element.
 9. The system of claim 1 wherein theelectrode has a contact surface area between 0.1 mm² and 20 mm².
 10. Thesystem of claim 1 wherein the electrode has a contact surface areabetween 0.01 mm² and 40 mm².
 11. The system of claim 1 wherein thestimulation is cathodic.
 12. The system of claims 1 wherein theelectrical stimulation includes a duty cycle comprising a set of burstsprovided in random or pseudo random fashion.
 13. The system of claim 1wherein the electrical stimulation includes a frequency range between0.1 Hz and 20 Hz.
 14. The system of claim 1 wherein the electricalstimulation results in a stochastic response of action potentials in thetargeted nerve fibers and no action potentials in the non-targeted nervefibers.
 15. The system of claim 1 wherein the targeted nerve fibers areafferent nerve fibers.
 16. The system of claim 1 wherein the targetednerve fibers are efferent nerve fibers.
 17. A method of reducing theperception of pain in a human comprising: providing the system of claim1; positioning the electrode at a therapeutically effective distancefrom the targeted nerve fibers; and electrically stimulating thetargeted nerve fibers to generate action potentials in the targetednerve fibers but without generating action potentials in non-targetednerve fibers.
 18. The method of claim 17 wherein the targeted nervefibers are afferent nerve fibers.
 19. The method of claim 17 wherein thetargeted nerve fibers are efferent nerve fibers.
 20. The method of claim17 wherein the step of electrically stimulating the targeted nervefibers results in a stochastic response.